Recent retrospective analyses indicate that the global burden of Shigella infections is >125 million annually [1, 2]. Shigellosis affects mainly children and causes at least 250,000 deaths per year. There are more than 40 serotypes of Shigella, but only a few are responsible for the majority of shigellosis. In developing countries, S. flexineri accounts for most of the case isolates in children under age 5, while S. sonnei is the second leading causative species, at about 24% [3]. In developed countries, S. sonnei is the leading cause of shigellosis. In United States alone, CDC estimates that there are about 500,000 cases every year; of which 75% are caused by S. sonnei. (reviewed in [4] and CDC, National Enteric Disease Surveillance: Shigella Annual Report, 2012.
In recent years, incidents of drug-resistant S. sonnei infection associated with international travellers and adult males who have sex with men have been increasingly reported [5-8]. Shigella is listed by both NIAID and DOD as a high priority pathogen.
Vaccines comprise a rational and cost-effective means for protecting against infectious diseases. Protection against shigellosis is believed to be based mainly on anti-O polysaccharide (or O antigen) antibodies [9].
Salmonella Typhi Ty21a typhoid vaccine (Vivotif®) [10] is the only live, oral, attenuated bacterial vaccine licensed in the US. Ty21a, when administered for a one week period, affords sustained protection from typhoid fever for 7 years with efficacies ranging from 62-96% as reported in Chilean/Egyptian field trials [11-13], and it has had an unrivaled safety record during the past 25 years [14-17]. There has never been a reported case of bacteremic dissemination of Ty21a after administration to more than 200 million recipients [10], and Ty21a is nonpathogenic even when given at 100 times the standard dose [12]. Also, there are no reports of post-vaccination inflammatory arthritis (e.g., Reiter's syndrome) with Ty21a, a potential problem with other live attenuated vectors including nontyphoid Salmonella, Shigella, and Yersinia. In addition, Ty21a can be foam-dried, which provides for temperature stabilization and a potential shelf life of 5-10 years [18].
Dr. Kopecko's lab used Ty21a as a vector to express S. sonnei form I O-antigen from an expression cassette inserted into plasmids (U.S. Pat. Nos. 7,541,043; 8,071,084; 8,337,832; and 8,992,943). Additionally, a recombinant Ty21a strain carrying a genome-integrated S. sonnei form I O-antigen gene cluster constructed in Dr. Kopecko's Lab induced high levels of serum antibodies against both S. sonnei form I O-antigen and Salmonella O9, 12 O-antigen and protected against lethal challenge of S. sonnei in mice [19 and WO2014/04367]. However, the immunization and infection route was by intraperitoneal (IP) injection, which is not the route for Ty21a immunization per se, nor is it the natural S. Typhi or S. sonnei route of infection. LPS alone immunized through the mucosal route is not immunogenic [20]. Moreover, high serum IgG does not directly reflect the strength of local mucosal immune responses.
Curtiss et al. described a bacterial recombinant comprising a Gad B/C acid resistance cassette [49].
There is a need for bivalent and multivalent transgenic attenuated, acid resistant vaccines for protection against shigellosis and typhoid fever.